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Fig. 1 · Structure
Cat. No.
A10549
CAS No.
167465-36-3
Formula
C32H31F2N3O2.3HCl
Mol. Weight
637

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LY335979 (Zosuquidar 3HCl)

Cat. No. A10549 CAS 167465-36-3

P-gp modulator

LY335979 (Zosuquidar trihydrochloride) is a potent highly selective P-gp inhibitor.

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Publications for LY335979

1 publication citing this product

  1. Leo Shen, .et al. , Sci Rep, 2021, Sep 16;11(1):18516 PMID: 34531456
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Biological Activity

Target & Activity

Target Activity Value
P-gp (Cell-free assay) Ki 60 nM

In Vitro Studies

In Caco-2 monolayers, zosuquidar 3HCl inhibited polarized etoposide transport, with apparent IC50 values of 5.80 ± 1.70 nM for secretory and 9.50 ± 5.61 nM for absorptive permeability. These assay-specific values use the paper’s free-molecule quantity convention. Extensive partitioning into cells and plates limits interpretation of nominal concentration as free drug exposure. [1]

Literature-reported observations and conditions; not Adooq-tested protocols or general treatment recommendations.

Inhibition of polarized etoposide transport across Caco-2 cells

Cell-based study · Caco-2 monolayers; bidirectional permeability of 50 μM etoposide [1]

Increasing apparent zosuquidar concentration reduced basolateral-to-apical permeability and increased apical-to-basolateral permeability. At 79 nM the authors reported abolition of polarized transport. Strong partitioning into cells and plates means applied concentrations differ from free concentrations; these IC50 values are assay-specific.

Measured endpoints — not treatment concentrations
EndpointReported resultReference
Apparent zosuquidar IC50 for modulation of basolateral-to-apical etoposide permeabilityIC50 5.80 ± 1.70 nM[1]
Apparent zosuquidar IC50 for modulation of apical-to-basolateral etoposide permeabilityIC50 9.50 ± 5.61 nM[1]
Zosuquidar recovered at 120 min in cell monolayer and cell culture platerecovery 58.7 ± 5.0% in cell monolayer; 31.8 ± 11.3% in plate[1]
Control efflux polarization and integrity checkstransport controls Without zosuquidar: efflux ratio 15.4 ± 1.3; lucifer yellow Papp <1.1 × 10−6 cm/s[1]

Literature-Reported Treatment Conditions

Treatment concentration
0.79 nM–2.5 μM apparent zosuquidar; 50 μM etoposide
Exposure duration
120 min; steady-state flux estimated over 30–120 min
Method
Bidirectional Caco-2 permeability; HPLC with fluorescence detection
Vehicle
10 mM HEPES HBSS pH 7.4; final 1% (v/v) methanol and 0.25% (v/v) DMSO
Co-treatment
Etoposide substrate; control without zosuquidar; lucifer yellow permeability and TEER integrity checks
Reported limits
The uncertainty type for Table 2 regression-parameter ± values is not explicitly identified in that table; it is not assigned SD or SEM here.
Methods and source locations

Compound reported in the paper: Zosuquidar (LY335979); Compound label in the paper: Zosuquidar 3HCl, Medkoo; quantities reported as free molecule without HCl

Cellular transport pharmacology of the reported material; no Adooq supplier/lot equivalence inferred.

Sections 2.1, 2.3, 2.3.2, 3.1-3.2; Fig. 1A-B and caption; Table 2

Apparent zosuquidar IC50 for modulation of basolateral-to-apical etoposide permeability: Nonlinear permeability regression; n = 4 individual cell passages for B-A. ± definition for fit parameters unspecified. — Sections 2.1, 2.3, 2.3.2, 3.1-3.2; Fig. 1A-B and caption; Table 2

Apparent zosuquidar IC50 for modulation of apical-to-basolateral etoposide permeability: Nonlinear permeability regression; n = 3 individual cell passages for A-B. ± definition for fit parameters unspecified. — Sections 2.1, 2.3, 2.3.2, 3.1-3.2; Fig. 1A-B and caption; Table 2

Zosuquidar recovered at 120 min in cell monolayer and cell culture plate: Mean ± SEM; pooled n = 3 passages × 4 concentrations × 2 directions = 24. Applied 79, 250, 790 nM or 2.5 μM. — Section 3.1; Fig. 1B caption

Control efflux polarization and integrity checks: Lucifer yellow permeability did not increase with zosuquidar; TEER fell on average 42%, with no filter falling >65%; authors judged layers intact. Efflux-ratio ± type unspecified in Results. — Sections 2.3.2 and 3.2; Fig. 1A

In Vivo Studies

In male Sprague-Dawley rats, oral zosuquidar co-administration increased oral etoposide exposure. At 63 mg/kg zosuquidar, etoposide bioavailability was 34.7 ± 5.3%, versus 5.51 ± 0.91% without zosuquidar (mean ± SEM; n = 6/group). The dose response was not monotonic, and a parallel IV-etoposide comparison showed reduced clearance. Three of six rats died in a separate 5 mg/kg IV-zosuquidar group; the authors raised a possible ethanol interaction without establishing the cause. The reported zosuquidar doses exclude the HCl component. [1]

Rat etoposide exposure during zosuquidar co-administration

Animal study · Male Sprague-Dawley rats; randomized ten groups of six; single-dose oral and IV disposition design [1]

Oral zosuquidar increased oral etoposide bioavailability at doses ≥0.63 mg/kg versus etoposide alone. The dose-response was not monotonic: 20 mg/kg produced lower mean bioavailability than 2.0 or 6.3 mg/kg. A parallel IV-etoposide comparator showed increased exposure with oral zosuquidar, so altered elimination contributes alongside absorption. Three deaths occurred in the separate IV-zosuquidar group, with an unresolved possible ethanol interaction.

Measured endpoints — not treatment concentrations
EndpointReported resultReference
Absolute etoposide bioavailability calculated from dose-normalized AUC0–6hbioavailability Control 5.51 ± 0.91%; with zosuquidar 0.063, 0.63, 2.0, 6.3, 20, 63 mg/kg: 4.99 ± 0.47%, 14.4 ± 2.5%, 22.4 ± 2.9%, 24.8 ± 2.7%, 20.5 ± 2.7%, 34.7 ± 5.3%, respectively[1]
Effect of oral zosuquidar 20 mg/kg on clearance of IV etoposide 5 mg/kgpharmacokinetics Clearance: 19.7 ± 1.1 versus 14.7 ± 0.8 mL/min/kg; AUC0–6h: 4.30 ± 0.25 versus 5.75 ± 0.30 μg/mL×h[1]
Early mortality after IV zosuquidar 5 mg/kgadverse observation 3/6 animals died shortly after IV administration[1]

Conditions shared by the study groups

Frequency
Single administration
Treatment course
Plasma sampling through 6 h
Study groups and reported outcomes
Group / doseComparatorObserved resultReference
IV etoposide reference
5 mg/kg etoposide		Reference for dose-corrected etoposide bioavailabilityEtoposide AUC0–6h 4.30 ± 0.25 μg/mL×h; n = 6[1]
IV etoposide with oral zosuquidar
5 mg/kg etoposide IV + 20 mg/kg zosuquidar oral		Group A: IV etoposide with oral vehicleEtoposide AUC0–6h 5.75 ± 0.30 μg/mL×h; n = 6; increased exposure and reduced clearance[1]
IV zosuquidar disposition and adverse outcome
5 mg/kg zosuquidar		Groups A/B ethanol-matched controls had no deaths or severe intoxication symptoms reportedThree of six animals died shortly after dosing; authors suggest possible potentiation of toxicity by zosuquidar and ethanol; cause not established[1]
Oral etoposide control
20 mg/kg etoposide; no zosuquidar		Comparator for oral co-administration groupsEtoposide bioavailability 5.51 ± 0.91%; n = 6[1]
Oral co-administration 0.063 mg/kg zosuquidar
20 mg/kg etoposide + 0.063 mg/kg zosuquidar		20 mg/kg oral etoposide without zosuquidar (group D)Etoposide bioavailability 4.99 ± 0.47%; mean ± SEM; n = 6; not significant versus group D[1]
Oral co-administration 0.63 mg/kg zosuquidar
20 mg/kg etoposide + 0.63 mg/kg zosuquidar		20 mg/kg oral etoposide without zosuquidar (group D)Etoposide bioavailability 14.4 ± 2.5%; mean ± SEM; n = 6; p < 0.05 versus group D[1]
Oral co-administration 2.0 mg/kg zosuquidar
20 mg/kg etoposide + 2.0 mg/kg zosuquidar		20 mg/kg oral etoposide without zosuquidar (group D)Etoposide bioavailability 22.4 ± 2.9%; mean ± SEM; n = 6; p < 0.05 versus group D[1]
Oral co-administration 6.3 mg/kg zosuquidar
20 mg/kg etoposide + 6.3 mg/kg zosuquidar		20 mg/kg oral etoposide without zosuquidar (group D)Etoposide bioavailability 24.8 ± 2.7%; mean ± SEM; n = 6; p < 0.05 versus group D[1]
Oral co-administration 20 mg/kg zosuquidar
20 mg/kg etoposide + 20 mg/kg zosuquidar		20 mg/kg oral etoposide without zosuquidar (group D)Etoposide bioavailability 20.5 ± 2.7%; mean ± SEM; n = 6; p < 0.05 versus group D[1]
Oral co-administration 63 mg/kg zosuquidar
20 mg/kg etoposide + 63 mg/kg zosuquidar		20 mg/kg oral etoposide without zosuquidar (group D)Etoposide bioavailability 34.7 ± 5.3%; mean ± SEM; n = 6; p < 0.05 versus group D[1]
IV etoposide reference
Model: Male Sprague-Dawley rats
Route: Intravenous
Vehicle: 30% ethanol oral vehicle; 40% ethanol IV solution
IV etoposide with oral zosuquidar
Model: Male Sprague-Dawley rats
Route: Oral zosuquidar 3–5 min before IV etoposide
Vehicle: Oral 30% ethanol and IV 40% ethanol
IV zosuquidar disposition and adverse outcome
Model: Male Sprague-Dawley rats
Route: Intravenous
Vehicle: Oral 30% ethanol vehicle and IV 40% ethanol
Reported limits: No mechanistic cause of group C deaths established.
Oral etoposide control
Model: Male Sprague-Dawley rats
Route: Oral gavage
Vehicle: 40% (v/v) ethanol
Oral co-administration 0.063 mg/kg zosuquidar
Model: Male Sprague-Dawley rats
Route: Oral gavage
Vehicle: 40% (v/v) ethanol
Oral co-administration 0.63 mg/kg zosuquidar
Model: Male Sprague-Dawley rats
Route: Oral gavage
Vehicle: 40% (v/v) ethanol
Oral co-administration 2.0 mg/kg zosuquidar
Model: Male Sprague-Dawley rats
Route: Oral gavage
Vehicle: 40% (v/v) ethanol
Oral co-administration 6.3 mg/kg zosuquidar
Model: Male Sprague-Dawley rats
Route: Oral gavage
Vehicle: 40% (v/v) ethanol
Oral co-administration 20 mg/kg zosuquidar
Model: Male Sprague-Dawley rats
Route: Oral gavage
Vehicle: 40% (v/v) ethanol
Oral co-administration 63 mg/kg zosuquidar
Model: Male Sprague-Dawley rats
Route: Oral gavage
Vehicle: 40% (v/v) ethanol
Methods and source locations

Compound reported in the paper: Zosuquidar (LY335979); Compound label in the paper: Zosuquidar 3HCl, Medkoo; dose quantities defined as free molecule

Rat pharmacokinetic co-administration evidence; no tumor efficacy, human benefit or Adooq material validation.

Sections 2.1, 2.5.1-2.5.2, 2.5.4-2.5.5, 3.4-3.5; Tables 1 and 3; Fig. 7 and caption

Absolute etoposide bioavailability calculated from dose-normalized AUC0–6h: Mean ± SEM; n = 6/group. One-way ANOVA with Dunnett test: doses ≥0.63 mg/kg p < 0.05 versus oral etoposide alone; 0.063 mg/kg not significant. — Sections 2.1, 2.5.1-2.5.2, 2.5.4-2.5.5, 3.4-3.5; Tables 1 and 3; Fig. 7 and caption

Effect of oral zosuquidar 20 mg/kg on clearance of IV etoposide 5 mg/kg: Without versus with oral zosuquidar; mean ± SEM, n = 6/group. Values from Table 3; no new statistical inference added. — Table 3 groups A/B; section 3.5; sections 2.5.2 and 2.5.4

Early mortality after IV zosuquidar 5 mg/kg: Separate group C; oral/IV ethanol vehicles; authors proposed possible potentiation of toxicity, not a proven cause. — Table 1 footnote; section 3.4 last toxicity paragraph

IV etoposide reference · Sections 2.1, 2.5.1-2.5.2, 2.5.4-2.5.5, 3.4-3.5; Tables 1 and 3; Fig. 7 and caption

IV etoposide with oral zosuquidar · Sections 2.1, 2.5.1-2.5.2, 2.5.4-2.5.5, 3.4-3.5; Tables 1 and 3; Fig. 7 and caption

IV zosuquidar disposition and adverse outcome · Sections 2.1, 2.5.1-2.5.2, 2.5.4-2.5.5, 3.4-3.5; Tables 1 and 3; Fig. 7 and caption

Oral etoposide control · Sections 2.1, 2.5.1-2.5.2, 2.5.4-2.5.5, 3.4-3.5; Tables 1 and 3; Fig. 7 and caption

Oral co-administration 0.063 mg/kg zosuquidar · Sections 2.1, 2.5.1-2.5.2, 2.5.4-2.5.5, 3.4-3.5; Tables 1 and 3; Fig. 7 and caption

Oral co-administration 0.63 mg/kg zosuquidar · Sections 2.1, 2.5.1-2.5.2, 2.5.4-2.5.5, 3.4-3.5; Tables 1 and 3; Fig. 7 and caption

Oral co-administration 2.0 mg/kg zosuquidar · Sections 2.1, 2.5.1-2.5.2, 2.5.4-2.5.5, 3.4-3.5; Tables 1 and 3; Fig. 7 and caption

Oral co-administration 6.3 mg/kg zosuquidar · Sections 2.1, 2.5.1-2.5.2, 2.5.4-2.5.5, 3.4-3.5; Tables 1 and 3; Fig. 7 and caption

Oral co-administration 20 mg/kg zosuquidar · Sections 2.1, 2.5.1-2.5.2, 2.5.4-2.5.5, 3.4-3.5; Tables 1 and 3; Fig. 7 and caption

Oral co-administration 63 mg/kg zosuquidar · Sections 2.1, 2.5.1-2.5.2, 2.5.4-2.5.5, 3.4-3.5; Tables 1 and 3; Fig. 7 and caption

Specifications

Manufacturer Adooq Bioscience
Actions Inhibitor
CAS Number 167465-36-3
Applications P-gp modulator
Formula C32H31F2N3O2.3HCl
Molecular Weight 637
Synonyms RS-33295-198; Zosuquidar 3HCl
SMILES
C1CN(CCN1C[C@H](COC2=CC=CC3=C2C=CC=N3)O)C4C5=CC=CC=C5[C@H]6[C@H](C6(F)F)C7=CC=CC=C47.Cl.Cl.Cl

Storage & Solubility

In Vitro Solubility

Reported Solubility

SolventReported Solubility
DMSO 93 mg/mL (145.99 mM)
Water 21 mg/mL (32.96 mM)
Ethanol Insoluble

Preparing Stock Solutions

Stock preparation is unavailable for this product molecular weight.

Calculated stock concentrations do not establish solvent solubility. Refer to the reported solubility data for experimental guidance.

In Vivo Preparation

Concentration
28 mg/mL
Vehicle
30% PEG400+0.5% Tween80+5% propylene glycol

Storage

Store powder at -20°C, keep desiccated.
In powder form, the chemical is stable for 36 months.
In solution, store at -20°C and use within 1 month to prevent loss of potency. Aliquot to avoid multiple freeze/thaw cycles.

Research References

  1. [1] Nielsen RB, Holm R, Pijpers I, et al. Oral etoposide and zosuquidar bioavailability in rats: Effect of co-administration and in vitro-in vivo correlation of P-glycoprotein inhibition. International journal of pharmaceutics: X (2021). PMID: 34977557 DOI: 10.1016/j.ijpx.2021.100089 Source material

Publications

1 publication citing this product

  1. Leo Shen, .et al. , Sci Rep, 2021, Sep 16;11(1):18516 PMID: 34531456

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